Acetaldehyde makes a distinct mutation signature in single-stranded DNA.
Acetaldehyde makes a distinct mutation signature in single-stranded DNA.
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DOI：
10.1093/nar/gkac570
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发表时间：
2022-07-22
影响因子：
14.9
通讯作者：
Saini, Natalie
中科院分区：
文献类型：
--
作者：
Vijayraghavan, Sriram;Porcher, Latarsha;Mieczkowski, Piotr A.;Saini, Natalie
乙醛（AA）是乙醇代谢的副产物，由于其能够与包括DNA和蛋白质在内的各种生物分子反应，因此具有急性毒性，这可以极大地阻碍复制和转录等关键过程并导致DNA损伤。因此，AA被国际癌症研究机构（IARC）归类为1组致癌物。先前的体外研究表明，AA在DNA上产生大体积加合物，具有以鸟嘌呤为中心（GG→TT）的突变。然而，由于其致突变性弱，化学半衰期短，缺乏强大的遗传试验，有相当大的变化，在报告体内的AA致突变作用。在这里，我们使用了一个建立的酵母遗传报告系统，并证明AA处理是高度致突变的细胞，并导致高频率的单链DNA（ssDNA）上的鸟嘌呤（G→T）链偏置突变。我们进一步证明，AA衍生的突变发生通过病变旁路上的ssDNA的translesion聚合酶Pol？最后，我们描述了一个独特的突变签名AA，然后我们确定在几个全基因组和外显子组测序的癌症，特别是那些与酒精消费。我们的研究提出了一个关键的机制，潜在的致癌作用的乙酰丙酮酸去诱变的单链DNA。
Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability to react with various biological molecules including DNA and proteins, which can greatly impede key processes such as replication and transcription and lead to DNA damage. As such AA is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous in vitro studies have shown that AA generates bulky adducts on DNA, with signature guanine-centered (GG→TT) mutations. However, due to its weak mutagenicity, short chemical half-life, and the absence of powerful genetic assays, there is considerable variability in reporting the mutagenic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA treatment is highly mutagenic to cells and leads to strand-biased mutations on guanines (G→T) at a high frequency on single stranded DNA (ssDNA). We further demonstrate that AA-derived mutations occur through lesion bypass on ssDNA by the translesion polymerase Polζ. Finally, we describe a unique mutation signature for AA, which we then identify in several whole-genome and -exome sequenced cancers, particularly those associated with alcohol consumption. Our study proposes a key mechanism underlying carcinogenesis by acetaldehyde—mutagenesis of single-stranded DNA.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.3
作者：
Brooks, PJ;Theruvathu, JA
通讯作者：
Theruvathu, JA
影响因子：
64.5
作者：
Haradhvala NJ;Polak P;Stojanov P;Covington KR;Shinbrot E;Hess JM;Rheinbay E;Kim J;Maruvka YE;Braunstein LZ;Kamburov A;Hanawalt PC;Wheeler DA;Koren A;Lawrence MS;Getz G
通讯作者：
Getz G
影响因子：
5.3
作者：
Jiang, GC;Sancar, A
通讯作者：
Sancar, A
DOI：
10.1093/bioinformatics/btv408
发表时间：
2015-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gehring JS;Fischer B;Lawrence M;Huber W
通讯作者：
Huber W